Device positionable in the uterine cavity and method of treatment thereof

ABSTRACT

A delivery vehicle for a silver ion source such as silver nitrate and the like, suitable for use in the treatment of menorrhagia, comprises a plurality of beads bearing a tissue cauterizing amount of a silver ion source. In some embodiments, the silver ion source is silver nitrate, in combination with a binder of hydroxy propyl cellulose and a diluent of potassium nitrate. In some embodiments, the plurality of beads is useful in treating menorrhagia of a mammalian uterus. Silver ions are delivered in a sufficient amount to the endometrium to cause necrosis of the endometrial tissue.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of International Patent ApplicationNo. PCT/IB2021/058603 filed Sep. 21, 2021, claiming the benefit ofcommonly owned U.S. Provisional Patent Application No. 63/081,028, filedon Sep. 21, 2020 and entitled “Device Positionable in the Uterine Cavityand Method of Treatment Thereof,” the contents of which are incorporatedherein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to a device positionable in the uterinecavity and use thereof for treating uterine-related disorders, such asmenorrhagia, by delivering tissue necrosing agents.

BACKGROUND

An intrauterine device (IUD) is a small device implanted in the uterinecavity and can be used for birth control and treatment ofuterine-related disorders by delivering tissue necrosing agents. Chronicabnormal uterine bleeding (AUB), involving menstrual bleeding ofabnormal quantity, duration, frequency, or regularity, is experienced by10-50% of women of reproductive age, adversely impacts quality of life,and can have substantial adverse economic impacts on patients andhealthcare systems. One of AUB's symptoms, heavy menstrual bleeding(HMB), can lead to iron deficiency, iron deficiency anemia, and in acuteand severe cases can necessitate emergency medical care. Whilepharmacologic treatment options exist, they are not always effective,and they are frequently associated with both side effects and ongoingcost of care. For example, a first-line treatment is hormonal treatmentusing oral contraceptives or a hormonal device. For example, asecond-line treatment is global endometrial ablation (GEA), whichrequires hospitalization and general anesthesia, is invasive, painful,and non-reversible (i.e., infertility).

Consequently, some women desire more definitive options. Endometrialablation (EA) is a minimally invasive approach designed to manage anumber of the causes of HMB and can be performed under directintrauterine vision with resectoscopic instruments or with anon-resectoscopic approach (non-resectoscopic endometrial ablation orNREA). For NREA, one of a number of specially designed devices isinserted into the endometrial cavity to deliver thermal, cryogenic orradiofrequency electrical energy in an attempt to destroy the uterinelining or endometrium. In some jurisdictions, NREA has become anaccepted office-based procedure, but is still usually performed in aninstitutional setting, is associated with risks associated with theprocedure, anesthesia, and subsequent infertility, and has a failurerate that averages about 26%. These devices are typically expensive andrequire training for both the surgeon and the ancillary support staff.

Silver nitrate (AgNO₃) is a colorless to transparent to whitecrystalline solid with no odor and a bitter metallic taste. A study byNeuwirth, et al. explored the safety, feasibility, and effectiveness ofsilver nitrate-dextran paste delivered through the cervix as a simpleand inexpensive endometrial ablation therapy for menorrhagia. Neuwirth RS, Singer A, Evaluation of a Silver Nitrate Endometrial Ablation FluidDelivery System as a Chemical Treatment for Menorrhagia, J MinimInvasive Gynecol. September-October 2013; 20(5):627-30. Neuwirth,however, discloses discontinuation of the studies of the silvernitrate-dextran paste delivery system because of the inability tocontrol the locus of caustic action. During the procedure, Neuwirthdiscloses one patient had silver nitrate paste spill through the leftfallopian tube into the peritoneal cavity. Thus, there is a need forsafe and effective delivery of tissue necrosing agents to the uterinecavity.

The present invention is a novel, three-dimensional endometrial ablationdevice and method developed to allow for chemical EA to treat the causesof the symptoms of HMB. The suggested procedure is expected to besimpler than the currently available EA methods and results in asignificative improvement in the patient bleeding pattern achievingclinically meaningful delay or abolishment of the need for hysterectomy.

BRIEF DESCRIPTION OF THE INVENTION

In some embodiments, the techniques described herein relate to anintrauterine device including: a wire having a portion capable offorming an elastically deformable three-dimensional structure; whereinthe three-dimensional structure: a) is elastically deformable to apartially collapsed configuration; b) has a crush force of at least 15grams/cm²; and c) is configured to elastically contract and expand inresponse to contraction and expansion of the uterine cavity, a pluralityof beads, including: 80% to 98% by weight of formulated activematerials, wherein the formulated active materials include 75% to 100%by weight of silver nitrate and 0% to 25% by weight of potassiumnitrate, wherein the ratio of potassium nitrate to silver nitrate isfrom 1:19 to 1:3, 2% to 20% by weight of a hydroxy propyl cellulosebinder; and two fixing beads, each positioned at opposite ends of thewire.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the plurality of beads is configured todisintegrate and form a paste-like material that spreads and covers auterine cavity when the plurality of beads is in contact with anendometrial lining of the uterus for a time period sufficient to necroseendometrial tissue.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the plurality of beads is notphysiologically inert.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the plurality of beads has an overallweight of between 0.6 grams and 1.0 grams.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein each bead including the plurality of beadshas a diameter of between 2.2 mm to 3.0 mm.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the two fixing beads are about 2 mm indiameter.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the material of the two fixing beads isselected from the group consisting of titanium, gold, and sterlingsilver.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the material of the two fixing beads istitanium.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein an Ag+ ion concentration of the silvernitrate is equal to c.a. 0.00334 Mol of Ag+.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the three-dimensional structure isconfigured to form two or more contiguous loops of the wire, which areangled with respect to each other.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the two or more contiguous loops of wireare 12 mm to 18 mm in diameter, respectively.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the two or more contiguous loops of wireare configured such that one loop is positioned within the plane of thesecond loop and is angled 60-120 degrees with respect thereto.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the wire is made of a super elasticmaterial.

In some embodiments, the techniques described herein relate to aintrauterine device, wherein the wire is made of nitinol.

In some embodiments, the techniques described herein relate to a methodof treating uterine-related disorders, including the steps of:Administering a plurality of beads to a uterine cavity of a humanpatient in need including: (i) from 75% to 100% by weight of silvernitrate and 0% to 25% by weight of potassium nitrate; and (ii) from 2%to 20% by weight of a hydroxy propyl cellulose binder; and maintainingthe plurality of beads in contact with an endometrial lining of theuterus for a time period sufficient to necrose endometrial tissue.

In some embodiments, the techniques described herein relate to a method,wherein the plurality of beads disintegrate and form a paste-likematerial that covers the endometrial lining of the uterus for a timeperiod sufficient to necrose endometrial tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

Illustrative examples of the present disclosure are described in detailbelow with reference to the attached drawing figures, which areincorporated by reference herein, and wherein:

FIG. 1 illustrate a uterine cavity in its relaxed state.

FIG. 2 illustrates, in some embodiments, the present device in itsthree-dimensional configuration.

FIG. 3 illustrates, in some embodiments, the device of FIG. 2 partiallycompressed by the forces of the relaxed uterine walls.

FIG. 4 illustrates, in some embodiments, a configuration of the deviceof FIG. 2 which includes a plurality of beads disposed on the wire.

FIG. 5 illustrates, in some embodiments, a delivery guide utilizable fordelivering the present device into a uterine cavity.

FIG. 6 a-c illustrate, in some embodiments, stepwise formation of thethree-dimensional structure of the present device as it is pushed out ofthe delivery guide in the uterine cavity.

The illustrated figures are exemplary only and are not intended toassert or imply any limitation with regard to the environment,structure, form, design, or process in which different examples may beimplemented.

DETAILED DESCRIPTION

In some embodiments, the present invention provides a device and methodof treatment suitable for delivering a silver ion source, such as silvernitrate and the like; a potassium source, such as potassium nitrate andthe like; and a binder, such as hydroxy propyl cellulose, to the uterinecavity of a patient suffering from menorrhagia to chemically necrose theendometrium. In some embodiments, the device and method of the presentinvention relates to patients suffering from chronic AUB or HMB, whichrefers to menstrual bleeding of abnormal quantity, duration, orschedule, a common gynecologic condition, occurring in approximately 10to 35% of women. Chronic heavy or prolonged uterine bleeding can resultin anemia, interfere with daily activities, and raise concerns aboututerine cancer.

In some embodiments, the delivery vehicle comprises a plurality of beadsbearing a solid silver ion source. In some embodiments, the solid silverion source adheres firmly to the plurality of beads, but the pluralityof beads readily releases a silver ion bearing composition when theplurality of beads come into contact with the moist endometrium of theuterus. In some embodiments, the plurality of beads comprises acomposition that is “consumed” or disintegrates after being placed inthe uterus—as such, the plurality of beads is not physiologically inert.

In some embodiments, the device contains a plurality of beads having asolid form of silver nitrate and/or silver nitrate and potassium nitratecombined with a soluble binder to keep the components together in asolid form. In some embodiments, once in contact with theendometrium/tissue/uterine fluid, the plurality of beads willdisintegrate and form a paste-like material that spreads and covers theuterine cavity. In some embodiments, the viscosity of the paste is suchthat it flows, but the paste does not spill out of the fallopian tubesor cervical os. The silver nitrate and/or silver nitrate and potassiumnitrate will cauterize the tissue (in a self-limiting manner due to itsbinding to and denaturing proteins) in a more controlled manner. Thus,the risk of spillage through the fallopian tubes, resulting incollateral organ damage, is significantly reduced.

The figures constitute a part of this specification and includeillustrative embodiments of the present invention and illustrate variousobjects and features thereof. Further, the figures are not necessarilyto scale, some features may be exaggerated to show details of particularcomponents. In addition, any measurements, specifications and the likeshown in the figures are intended to be illustrative, and notrestrictive. Therefore, specific structural and functional detailsdisclosed herein are not to be interpreted as limiting, but merely as arepresentative basis for teaching one skilled in the art to variouslyemploy the present invention.

Among those benefits and improvements that have been disclosed, otherobjects and advantages of this invention will become apparent from thefollowing description taken in conjunction with the accompanyingfigures. Detailed embodiments of the present invention are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely illustrative of the invention that may be embodied in variousforms. In addition, each of the examples given in connection with thevarious embodiments of the invention which are intended to beillustrative, and not restrictive.

Throughout the specification and claims, the following terms take themeanings explicitly associated herein, unless the context clearlydictates otherwise. The phrases “in one embodiment” and “in someembodiments” as used herein do not necessarily refer to the sameembodiment(s), though it may. Furthermore, the phrases “in anotherembodiment” and “in some other embodiments” as used herein do notnecessarily refer to a different embodiment, although it may. Thus, asdescribed below, various embodiments of the invention may be readilycombined, without departing from the scope or spirit of the invention.

As used herein “an intrauterine device” refers to any device implantablewithin the uterine cavity, preferably via delivery through the vaginalcavity and cervix. As is further described herein, such a device ispreferably configured for releasing an active agent capable ofpreventing pregnancy (contraceptive or birth control IUD) or treating auterine disorder such as menorrhagia or medical or surgical therapy toendometrium or myometrium for any length of time including minutes,hours, days, weeks, months or years.

As used herein the term “about” refers to ±10%.

In its relaxed state, the cavity of the uterus is a mere slit havingsubstantially no volume (FIG. 1 ). During uterine contractions, theuterine walls relax and contract upon each other. When relaxed, theuterine walls exert an inward force of 10 mmHg (about 13.5 grams cm2),however, under contractions, inward forces exerted by the uterine wallscan rise to as much as 50-60 mmHg (about 67-82 grams/cm2) and higher(Gestel et al. Human Reproduction Update, Vol. 9, No. 2 pp. 131-138,2003).

In some embodiments, there is provided an intrauterine device. In someembodiments, the device includes a wire having a portion capable offorming an elastically deformable three-dimensional structure.

In some embodiments, the wire can be composed of a selected superelastic material capable of being pre-shaped into the three-dimensionalstructure and being linearized by a pulling force on the ends of thewire. In some embodiments, such a transition between three-dimensionaland linear configurations can be effected repeatedly due to the elasticnature of the material and its ability to maintain the three-dimensionalshape in the absence of any pulling force on the ends of the wire (e.g.,shape memory).

In some embodiments, examples of materials suitable for the wireinclude, but are not limited to, alloys such as stainless steel,nickel-titanium, copper-aluminum-nickel and other copper containingalloys or polymers such as polyurethanes, polyols, polyethyleneterephthalates and acrylates.

In some embodiments, the wire can be 50-100 mm long with the portionforming the three-dimensional structure being 50-100% of the overalllength (10-100 mm).

In some embodiments, the three-dimensional structure of the presentdevice is formed by two or more contiguous loops of the wire which areangled with respect to each other. In some embodiments, the loops can be12-18 mm in diameter and are arranged (in a two loop configuration) suchthat one loop is positioned within the plane of the second loop and isangled 60-120 degrees, preferably 80-100 degrees, with respect thereto(the angle is measured at the wire portion interconnecting the loops).In some embodiments, thus, the loops form a loop-in-loop structure that‘traps’ a roughly spherical volume of 0.9-3.0 cm3 (1-1.5 cm3 preferred)with a surface area of 4.5-10.1 cm2 (6-8 cm2 preferred). Furtherdescription of the three-dimensional structure and formation of theloops from the linear/linearized wire is provided hereinbelow.

In some embodiments, the device of the present invention is athree-dimensional spherical frame measuring about 16 mm in diameter andweighing a total of about 1 gram. In some embodiments, the device isconstructed with a frame which is made of super elastic nitinol alloywhich once deployed from the insertion tube into the uterine cavitycoils into a three-dimensional spherical shape. In some embodiments, athread (e.g., monofilament nylon) is tied through the tip, resulting intwo threads, each, for example, 20 to 30 cm in length, for removal ofthe device. In some embodiments, two fixing beads are threaded andsqueezed at opposite ends of the nitinol wire to serve as physicallimiters, holding the plurality of silver nitrate and/or silver nitrateand potassium nitrate beads in place.

In some embodiments, the present device was designed in order to improvethe stability of a previous design. In order to provide the requisitestability, in some embodiments, the present inventors have uncoveredthat a wire diameter of 0.3-1.0 mm, preferably 0.4-0.6 mm, combined witha device overall diameter of 12-20 mm result in elastic resistance towall forces of a relaxed uterus and a slight device shape change undersuch forces, while enabling the device to contract and expand along withan active uterus (and nearly completely flatten under strongcontractions). Although the present device applies a counter force tothe relaxed uterine walls, such a counterforce does not result in tissueirritation and does not lead to any discomfort.

In some embodiments, the plurality of beads is substantially sphericalin shape and have an average diameter in the range of about 1 to about 6mm, more preferably about 2 to about 4 mm.

In some embodiments, the plurality of beads is prepared by mixing 90% offormulated active materials (75% silver nitrate and 25% potassiumnitrate) with a binder 10% on a weight basis. In some embodiments, thismixture is further dried to form a paste. In some embodiments, the pasteis divided into pre-determined size pieces that are molded, using aspecially designed mold, into beads. In some embodiments, a uniform sizehole is created in each bead. In some embodiments, the plurality ofbeads is further dried and solidified in an oven.

In some embodiments, the device contains 28 to 32 beads with an overallweight of 0.6 to 1.0 grams. In some embodiments, the overall weight ofthe plurality of beads is about 0.7 to 0.9 grams. In some embodiments,the overall weight of the plurality of beads is about 0.8 to 0.9 grams.In some embodiments, the individual weight of the plurality of beads is0.02 to 0.04 grams. In some embodiments, the individual weight of theplurality of beads is 0.03 grams.

In some embodiments, each of the plurality of beads is between about 2mm to 3 mm in diameter. In some embodiments, each of the plurality ofbeads is between about 2.1 mm to 2.9 mm in diameter. In someembodiments, each of the plurality of beads is between about 2.2 mm to2.8 mm in diameter. In some embodiments, each of the plurality of beadsis between about 2.3 mm to 2.7 mm in diameter. In some embodiments, eachof the plurality of beads is between about 2.4 mm to 2.6 mm in diameter.In some embodiments, each of the plurality of beads is between about 2.7mm to 2.8 mm in diameter.

In some embodiments, the Ag+ ion concentration is equal to c.a. 0.00334Mol of Ag+(empirical measurement by titration). In some embodiments, thedevice contains a plurality of at least 14 beads (average weight 0.8grams) of the formulated active materials of which 75% (approximately0.54 grams) is silver nitrate. In some embodiments, the device containsat least 10 to 40 beads. In some embodiments, the device contains aplurality of at least 14 to 36 beads. In some embodiments, the devicecontains a plurality of at least 18 beads to 32 beads. In someembodiments, the device contains a plurality of at least 22 to 28 beads.In some embodiments, the device contains a plurality of at least 25beads to 30 beads. In some embodiments, the device contains an averageof 0.80 grams of the active materials of which 75% (0.54 grams) issilver nitrate. In some embodiments, the ratio of potassium nitrate tosilver nitrate is from 1:19 to 1:3. In some embodiments, the ratio ofpotassium nitrate to silver nitrate is 1:3.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (75% silver nitrate and25% potassium nitrate) and 10% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 80% to 98% of formulatedactive materials (75% silver nitrate and 25% potassium nitrate) and 2%to 20% HPC on a weight basis. In some embodiments, the plurality ofbeads comprises: 85% to 93% formulated active materials (75% silvernitrate and 25% potassium nitrate) and 7 to 15% HPC on a weight basis.In some embodiments, the plurality of beads comprises: 88% to 91%formulated active materials (75% silver nitrate and 25% potassiumnitrate) and 9% to 12% HPC on a weight basis.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (80% silver nitrate and20% potassium nitrate) and 10% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 80% to 98% of formulatedactive materials (80% silver nitrate and 20% potassium nitrate) and 2%to 20% HPC on a weight basis. In some embodiments, the plurality ofbeads comprises: 85% to 93% formulated active materials (80% silvernitrate and 20% potassium nitrate) and 7 to 15% HPC on a weight basis.In some embodiments, the plurality of beads comprises: 88% to 91%formulated active materials (80% silver nitrate and 20% potassiumnitrate) and 9% to 12% HPC on a weight basis.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (85% silver nitrate and15% potassium nitrate) and 10% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 80% to 98% of formulatedactive materials (85% silver nitrate and 15% potassium nitrate) and 2%to 20% HPC on a weight basis. In some embodiments, the plurality ofbeads comprises: 85% to 93% formulated active materials (85% silvernitrate and 15% potassium nitrate) and 7 to 15% HPC on a weight basis.In some embodiments, the plurality of beads comprises: 88% to 91%formulated active materials (85% silver nitrate and 15% potassiumnitrate) and 9% to 12% HPC on a weight basis.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (90% silver nitrate and10% potassium nitrate) and 10% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 80% to 98% of formulatedactive materials (90% silver nitrate and 10% potassium nitrate) and 2%to 20% HPC on a weight basis. In some embodiments, the plurality ofbeads comprises: 85% to 93% formulated active materials (90% silvernitrate and 10% potassium nitrate) and 7 to 15% HPC on a weight basis.In some embodiments, the plurality of beads comprises: 88% to 91%formulated active materials (90% silver nitrate and 10% potassiumnitrate) and 9% to 12% HPC on a weight basis.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (95% silver nitrate and5% potassium nitrate) and 10% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 80% to 98% of formulatedactive materials (95% silver nitrate and 5% potassium nitrate) and 2% to20% HPC on a weight basis. In some embodiments, the plurality of beadscomprises: 85% to 93% formulated active materials (95% silver nitrateand 5% potassium nitrate) and 7 to 15% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 88% to 91% formulatedactive materials (95% silver nitrate and 5% potassium nitrate) and 9% to12% HPC on a weight basis.

In some embodiments, the plurality of beads comprises a compositioncomprising: 90% of formulated active materials (100% silver nitrate) and10% HPC on a weight basis. In some embodiments, the plurality of beadscomprises: 80% to 98% of formulated active materials (100% silvernitrate) and 2% to 20% HPC on a weight basis. In some embodiments, theplurality of beads comprises: 85% to 93% formulated active materials(100% silver nitrate) and 7 to 15% HPC on a weight basis. In someembodiments, the plurality of beads comprises: 88% to 91% formulatedactive materials (100% silver nitrate) and 9% to 12% HPC on a weightbasis.

In some embodiments, the average inner surface area of the human uteruswas calculated to be approximately 12 cm2 based on cavimeter uterinesize measurements. In some embodiments, each 1 cm2 of the inner uterinesurface will potentially be exposed to about 45.0 mg of silver nitrate.In some embodiments, the device contains approximately 0.0032 moles ofAg+ ions reflecting an average of 2.7×1015 Ag+ ions. In someembodiments, using the same human uterus inner surface area calculationreferred to above, each 1 cm2 is exposed to 2.3×1014 Ag+ ions.

In some embodiments, the binder or binding agent, is prepared from asolution of 20% w/w hydroxy propyl cellulose (HPC) and 80% w/w ethanol.In some embodiments, HPC is a hydrogel. In some embodiments, HPC has amolecular weight of approximately 100 kD. In some embodiments, HPC has amolecular weight of approximately 60 to 160 kD. In some embodiments, HPChas a molecular weight of approximately 80 to 140 kD. In someembodiments, HPC has a molecular weight of approximately 100 to 120 kD.In some embodiments, HPC improved delivery and provided optimizedcoverage in the uterine cavity when used as a system, e.g., when usedwith silver nitrate and potassium nitrate. In an embodiment, the amountof active material in the form of solid silver nitrate beads achievescomplete coverage of the entire inner surface of the uterus.

In some embodiments, each of the plurality of beads has the samegeometry. In some embodiments, one or more of the plurality of beads hasa different geometry. In some embodiments, each of the plurality ofbeads may be any conventional bead shape including, but not limited to,sphere, cylinder, cone, regular polyhedron, irregular polyhedron, orother suitable geometry to achieve the desired contraceptive ortreatment outcome disclosed herein.

In some embodiments, the plurality of beads can be threaded or slidablymounted over the wire and freely move thereon in which case theplurality of beads include a central through-hole (0.4-1.1 mm indiameter), and/or they can be fixedly attached to the wire via anadhesive, or crimping. In some embodiments, the plurality of beads arethreaded over a nitinol wire frame and remain on the frame by using twofixing beads. In some embodiments, examples of materials suitable forthe fixing beads include, but are not limited to, titanium, gold, andsterling silver.

In some embodiments, the fixing beads are between 1 mm and 3 mm indiameter. In some embodiments, the fixing beads are about 2 mm indiameter. In some embodiments, the fixing beads have the same geometry.In some embodiments, the fixing beads each has a different geometry. Insome embodiments, the fixing beads may be any conventional bead shapeincluding, but not limited to, sphere, cylinder, cone, regularpolyhedron, irregular polyhedron, or other suitable geometry to achievethe desired contraceptive or treatment outcome disclosed herein.

In some embodiments, a monofilament nylon removal thread is tied to theend of the frame. A configuration of the present device which includesfixed and freely moving beads is illustrated in FIG. 4 , which isdescribed in greater detail below.

Referring now to the drawings, FIG. 2 illustrates one embodiment of thepresent device which is referred to herein as device 10.

Device 10 includes a wire 12, which has beads 22 disposed over the wire12, forming a three-dimensional structure 14 from a first loop 16contiguous with a second loop 18. The ends of wire 12 (indicated by E)are turned inward in the direction of the volume defined by loops 16 and18 of device 10. To illustrate the ends of the wire 12 (indicated by E)fixing beads 24 and 26 (FIG. 4 ) are not pictured. Any of ends E can beconnected to a pull string 57 (FIGS. 3 and 5 ) for loading device 10into a delivery guide (not pictured) and for removing device 10 from thebody. Such a pull string can be fabricated from nylon, polypropylene orpolyethylene attached to wire 12 via gluing crimping etc. The functionof pull string 57 is described hereinbelow.

Loops 16 and 18 are connected via a contiguous segment 20 which forms anangle ‘A’ between loops 16 and 18; angle ‘A’ can be 80-100 degrees.

The overall diameter of device 10 (D) can be 12-15 mm, preferably 13 mm.Loops 16 and 18 are substantially of equal diameter (d) of 12-18 mm,preferably 13 mm. The diameter of wire 12 (wd) can be 0.4-1.0 mm,preferably 0.6 mm.

As is mentioned hereinabove, device 10 is configured to partiallycompress under the forces applied by the walls of a relaxed uterinecavity.

For example, a device 10 having an overall diameter of 13 mm constructedfrom a Nitinol wire (0.5 mm in diameter) formed into two contiguousloops (13 mm in diameter) an angled at 90 degrees with respect to eachother would partially collapse under a force of 13.6 grams/cm2 to form aroughly oval shape (FIG. 3 ) with a height of 10 mm. When partiallycollapsed, device 10 applies an elastic counterforce to the walls of theuterine cavity thus firmly securing device 10 in position. Nearflattening of this configuration of device 10 would require about 50-60grams/cm2.

Collapse of device 10 under such forces is influenced by two separate orcombined mechanisms, change in angle A (elastic bending at segment 20)and shape change (round to oval) in each of loops 16 and 18 (elasticbending of the loops).

Collapse along one axis of device 10 is primarily mediated by segment 20which can bend under relatively lower forces (exerted by relaxed uterinewalls). Such collapse enables device 10 to assume the oval-shapedconfiguration described above. Collapse along other axis requires alarger force (uterine contractions) since it necessitates a shape-change(round to oval) in loops 16 and 18 (as well as further bending ofsegment 20).

Collapse through a combination of axis is also possible and will dependon the orientation of device 10 in the uterine cavity and type ofcontractions.

FIG. 4 illustrates a configuration of device 10 which includes aplurality of beads 22 disposed over wire 12. As is mentionedhereinabove, plurality of beads 22 can be fixed to, and/or they canfreely move upon wire 12. In the configuration shown in FIG. 4 , fixingbeads 24 and 26 are fixed to ends of wire 12, while the plurality ofbeads 22 in-between freely moves along wire 12.

Fixing beads 24 and 26 while allowing the plurality of beads 22(in-between beads 24 and 26) to freely slide upon wire 12 may provideseveral advantages. Fixing beads 24 and 26 protect (and blunt) the endsof wire 12 thus minimizing the chances of tissue perforation duringdelivery and precludes any sharp edges from irritating or piercingtissue during the course of use.

Allowing the plurality of beads 22 (in-between beads 24 and 26) tofreely slide on wire 12 may optimize contact between the plurality ofbeads 22 and the uterine wall thus maximizing contact between the activeagent contained therein and the tissue wall as well as reducingpotential irritation that may be caused by a stationary bead during thecourse of use.

Device 10 can be fabricated by winding a wire (e.g., nitinol) around amold (e.g., mandrel) capable of maintaining the wire in the desiredform. The mold and wound wire are then heated or chemically treated fora specified time to set the wire in the molded shape and the shaped wireis removed from the mold. The formed wire structure can then be coatedand/or beads can be threaded thereupon with a leading and trailing beadpermanently attached to the wire via soldering. Any excess wireprotruding past the leading or trailing bead can then be trimmed.

Delivery and implantation of device 10 in the uterine cavity ispreferably carried out using a dedicated delivery guide.

FIG. 5 illustrates one configuration of such a delivery guide which isreferred to herein as guide 50.

Guide 50 includes a hollow tube 52 having a distal opening 53 and aproximal opening 55 defining a lumen therebetween. Wire 12 with amounted plurality of beads 22 and attached pull string 57 is linearizedand positioned within the lumen of tube 52. Device 10 can be loaded intothe lumen by threading pull string 57 into lumen and pulling it throughthereby linearizing the three-dimensional structure formed by wire 12 asit is pulled into the lumen. A typical pulling force required for suchlinearization can be 100-150 grams.

Guide 50 also includes a plunger 54 having a shaft 58 fitted with ahandle 56. Plunger shaft 58 fits into the lumen of tube 52 throughproximal opening 55. Handle 56 is used to advance shaft 58 within thelumen of tube 52 thus advancing wire 12 with a plurality of fitted beads22 out of distal opening 53 incrementally forming the two-loopthree-dimensional structure of the present device.

FIGS. 6 a-c illustrate delivery of device 10 into a uterine cavity usingdelivery guide 50.

Distal opening 53 (not shown in FIGS. 6 a-c ) of guide 50 ispositionable in the uterine cavity by measuring uterine depth prior toinsertion using a hysterometer (sound). The measured depth from thefundus to the external ostium of the cervical canal is determined byadjusting a slider or flange to the desired length of the tube. In someembodiments, the measured depth from the fundus to the external ostiumof the cervical canal is marked on tube 52 as reference to the insertiondepth of guide 50.

Plunger 54 (FIG. 5 ) is then used to advance wire 12 and attachedplurality of beads 22 out of distal opening 53 (FIG. 5 ) as is shown inFIGS. 6 a-c , thereby forming the first loop (FIG. 6 b ) and contiguoussecond loop (FIG. 6 c ) of the 3D structure of device 10 from the linearwire. Delivery guide 50 is then removed from the body leaving behinddevice 10 in the uterus and attached pull string 57, the proximal end ofwhich is positioned at the vaginal canal.

Delivery guide 50 can also include an attached light source (e.g., LEDor fiber optic light) in order to illuminate the uterine cavity withwhite light or light of a specific wavelength (e.g., blue light).Delivery guide can also include a camera for imaging the uterine cavityin 3D instead of using a hysteroscope.

In some embodiments, a method of treating menorrhagia is disclosedcomprising the steps of administering to the uterine cavity of a patientsuffering from menorrhagia a plurality of beads bearing a tissuecauterizing amount of a solid silver ion source such as silver nitrateand the like; and maintaining the plurality of beads in contact with theendometrial lining of the uterus for a time period sufficient to necrosethe endometrial tissue.

In some embodiments, the method of treatment of the present inventionreduces one or more of the following indications: intrauterine treatmentof disorganized proliferative (benign) endometrial conditions resultingin AUB; intrauterine treatment of menorrhagia (menstrual periods withabnormally heavy or prolonged bleeding) and metrorrhagia (irregularbleeding); and/or intrauterine treatment of Endometrial Hyperplasia.

In some embodiments, the device and method of treatment of the presentinvention causes local tissue cauterization of the endometrium byutilizing the cauterization properties of a solid form of the causticagent silver nitrate. Once deployed from the insertion tube, theplurality of beads disintegrates, spread in the uterine cavity andchemically ablate the endometrium upon direct contact. In someembodiments, following 30 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, following 20 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, following 25 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, following 35 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, following 40 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, following 45 minutes of treatment, the device is removedfrom the uterine cavity by the attached removal threads. In someembodiments, after the device is removed from the uterine cavity, thecervix is washed with saline solution. In some embodiments, the salinesolution contains 0.9 w/v % of chlorine ions. Any remaining silver ionsbecome inactive after contacting with the endometrial tissue, uterinefluid and body exudates, which are rich in chlorine ions. The formedcomplex deactivates the silver ion resulting in silver chloride, anon-dissolvable salt, that will be washed out in a few days or with thenext menses.

In some embodiments, the method of treatment comprises the steps of:deploying the device within the uterine cavity environment, resuming thedevice predetermined three-dimensional spherical shape, and maintainingthe device within the uterine cavity so the plurality of beadsdisintegrates in the uterus resulting in the silver nitrate coming incontact with the uterine endometrium tissue and resulting incauterization of the uterine endometrium tissue. One advantage of thepresent invention is that the silver nitrate cauterization mechanism isself-limiting because the silver ions oxidize tissue proteins tosilver-proteinate which then reacts with chlorides and sulfides to formdark colored, inactive, insoluble compounds (colorants). As such, thesilver nitrate becomes inactive within 2 to 50 minutes (e.g., 5 to 45minutes, 10 to 40 minutes, 15 to 35 minutes or 20 to 30 minutes), sothat when the device is removed no active material remains in thesubject's uterus.

In some embodiments, the method of treatment comprises the followingsteps:

measuring the uterine depth of a patient;

marking the distance with a flange from the top of a loaded insertiontube, wherein the device is contained within the loaded insertion tube,as the uterine depth of the patient;

passing the loaded insertion tube through the cervical canal of thepatient until the flange reaches the outer cervical opening so that thetip of the insertion tube is touching the uterine fundus;

pulling back the insertion tube 3-5 mm;

releasing the device into the uterine cavity by holding the insertiontube without pulling the insertion tube out and pushing a rod all theway into the uterine cavity;

removing the rod and the insertion tube; and

removing the device after X minutes (wherein X is about 15 to 45minutes).

Additional objects, advantages, and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting.

EXAMPLES

The present disclosure can be better understood by reference to thefollowing examples, which are offered by way of illustration. Thepresent disclosure is not limited to the examples given herein.

Example 1

The device contains a plurality of beads. This example discloses thepreparation of the plurality of beads having a solid form of formulatedactive materials (i.e., salt components) combined with a soluble binder.In this example, 90% of formulated active materials are combined with10% of a binder on a weight basis. The binder or binding agent, isprepared from a solution of 20% w/w hydroxy propyl cellulose (HPC) and80% w/w ethanol. Thus, the starting materials are 90% w/w saltcomponents, 2% w/w HPC and 8% w/w ethanol. The binder solution isprepared and conditioned for 2-3 days before mixture with the formulatedactive materials. The binder solution is dried at 70 to 80° C. toevaporate the ethanol to result in the final HPC binder. In thisexample, after complete drying, 2.2% w/w HPC and 97.8% w/w saltcomponents are present.

Example 2

A phase I clinical study, recruiting up to 10 women, was designed toevaluate the safety and efficacy of device disclosed herein. Thesubjects were scheduled to undergo hysterectomy due to AUB of benigncauses, who failed or could not tolerate medical therapy (1st line) orwho preferred treatment options not requiring frequent dosing. Theinvestigational treatment involved a thirty minute endometrial ablationsession using the device, executed in the operating room, immediatelyfollowed by the planned hysterectomy procedure.

Efforts were made to recruit an equal number of women with highendometrial thickness (>7 mm) and low endometrial thickness (<7 mm). Onthe day of surgery, the subject underwent a vaginal ultrasound, tore-measure the endometrial thickness, and hysteroscopy, to visualize theuterine cavity and the endometrium. The device was inserted, undergeneral anesthesia and under uterine visualization, into the uterinecavity via the vagina, and left in the uterus for 30 minutes. The devicewas removed via the vagina and while the cervix was flushed with normalsaline. Once the device was removed, the planned surgical hysterectomywas performed.

After surgery, the extracted uterus was immediately evaluated by thestudy pathologist for gross pathology and silver nitrate coverage of theendometrium and was later subjected to pathology (macroscopic analysesof the intra-uterine cavity and microscopic analyses of the multiplesections of the uteri) histopathological evaluations to define theextent of active material endometrium coverage and endometrial ablation.

Macroscopic pathological analysis of the uteri demonstrated intensestaining of the endometrium by silver nitrate, with a high degree ofcoverage. No staining of the fallopian tubes was reported. Microscopicevaluations were conducted by a certified human pathologist, using asystematic approach of creating blocks and hematoxylin & eosine stainedslides from different areas of the uterus. The specimens demonstratedextensive denuding of the superficial-functional layer of theendometrium, with sloughing into the uterine cavity. The remainingsuperficial-functionalis layer showed varying degrees of detachment,disintegration of glands, congestion and hemorrhage. The depth andextent of damage varied across the tissue within and between patients.The basalis layer had various degrees of disrupted glands, dilated andcongested blood vessels and hemorrhages. High variability in the depthand extent of damage to the basalis layer was observed in the samepatient and between patients.

Several cases of small “crater-like areas” where the endometrium wasabsent, were reported. In most cases, the superficial myometriumcontained dilated and mildly congested blood vessels, with no tissuedamage.

There was a strong correlation between localization of the silvernitrate and observed damage. The cervix showed superficial silvernitrate staining, with no damage to the columnar epithelium and nopathological findings. Histological analysis showed no damage to eitherthe cervical canal, vagina, or the internal organs. No spillage via thefallopian tubes was reported. A strong correlation was noted betweenlocalization of the silver nitrate and observed damage to the targetedendometrium, with the degree of damage varying between the subjects andthe different uterine section. In all patients, following macroscopicevaluation, silver nitrate was demonstrated in the entire uterinecavity, covering the entire endometrium. Taken together, silver nitrateelicited the expected cauterization effect.

Example 3

A Phase IIA randomized, perspective pre-pivotal study was designed toassess the safety and performance of the device disclosed herein and theablation procedure. The study was performed in an outpatient setting inwomen suffering from AUB, with follow up for 12 months post-treatment.The subjects underwent a 30-min endometrial ablation session using thedevice disclosed herein, in a hospital outpatient clinic. There were twocohorts. Cohort I comprised women experiencing a sub-optimal treatmentresponse (at least 3 months and no later than 12 months after the firsttreatment) who were eligible to receive a second treatment using thedevice disclosed herein. Cohort II comprised women who underwent asecond treatment session within 7 days following cessation of their nextmenses or, in cases where menstruation could not be defined, 28-29 daysfollowing the first treatment session. The patients were randomized tocohort I and cohort II. The average patient age was 42 years, averagebaseline Pictorial Blood Loss Assessment Chart (PBAC) was 541 andquality of life (QoL) (measured by Short Form 12 (SF12)) was 39.

The device used in the Phase IIA trial was a three-dimensional sphericalframe measuring about 16 mm in diameter and weighing a total of about 1gram. It is comprised of a super elastic memory shaped nitinol alloyframe which, once deployed from the insertion tube into the uterinecavity, coils into a three-dimensional spherical shape. A monofilamentnylon thread is tied through the tip, resulting in two threads, each20-30 cm in length, for removal of the device. Thirty (30) solidspherical shaped silver nitrate beads, each 3 mm in diameter weighingtogether an average of 0.81 grams, are threaded over the device frame infree motion. Two titanium beads (2 mm in diameter) are threaded andsqueezed at both ends of the nitinol wire to serve as physical limitersto prevent the silver nitrate cylinders from falling off.

The preliminary results showing a PBAC comparison between baseline and 6months post-treatment is available, which is presented in Table 1.

TABLE 1 PBAC PBAC at % Patient Baseline 6 Months reduction 01-003 602536 11% 01-002 201 83 59% 01-010 214 14 93% 01-008 593 18 97% 01-007 3320 100%  02-006 510 26 95% 02-008 254 2 99% 02-002 500 111 78% 02-009 382112 71% 01-011 420 58 86% 02-013 672 90 87% 02-014 246 31 87% 02-016 672140 79% 02-020 331 20 94% Average 424 89 81%

To date, no major safety issues have been raised.

One or more illustrative examples incorporating the examples disclosedherein are presented. Not all features of a physical implementation aredescribed or shown in this application for the sake of clarity.Therefore, the disclosed systems and methods are well adapted to attainthe ends and advantages mentioned, as well as those that are inherenttherein. The particular examples disclosed above are illustrative only,as the teachings of the present disclosure may be modified and practicedin different but equivalent manners apparent to those skilled in the arthaving the benefit of the teachings herein. Furthermore, no limitationsare intended to the details of construction or design herein shown otherthan as described in the claims below. It is therefore evident that theparticular illustrative examples disclosed above may be altered,combined, or modified, and all such variations are considered within thescope of the present disclosure. The systems and methods illustrativelydisclosed herein may suitably be practiced in the absence of any elementthat is not specifically disclosed herein and/or any optional elementdisclosed herein.

Although the present disclosure and its advantages have been describedin detail, it should be understood that various changes, substitutionsand alterations can be made herein without departing from the spirit andscope of the disclosure as defined by the following claims.

What is claimed is:
 1. An intrauterine device comprising: a wire havinga portion capable of forming an elastically deformable three-dimensionalstructure; wherein the three-dimensional structure: a) is elasticallydeformable to a partially collapsed configuration; b) has a crush forceof at least 15 grams/cm²; and c) is configured to elastically contractand expand in response to contraction and expansion of the uterinecavity, a plurality of beads comprising: 80% to 98% by weight offormulated materials, wherein a ratio of potassium nitrate to silvernitrate is 1:3, 2% to 20% by weight of a hydroxy propyl cellulosebinder, wherein each of the plurality of beads is not physiologicallyinert such that each of the plurality of beads is configured tocompletely disintegrate and form a paste material that spreads andcovers a uterine cavity when the plurality of beads is in contact withan endometrial lining of the uterus for a time period sufficient tonecrose endometrial tissue; and two fixing beads, each positioned atopposite ends of the wire.
 2. The intrauterine device of claim 1,wherein the plurality of beads is not physiologically inert.
 3. Theintrauterine device of claim 1, wherein the plurality of beads has anoverall weight of between 0.6 grams and 1.0 grams.
 4. The intrauterinedevice of claim 1, wherein each bead in the plurality of beads has adiameter of between 2.2 mm to 3.0 mm.
 5. The intrauterine device ofclaim 1, wherein the two fixing beads are about 2 mm in diameter.
 6. Theintrauterine device of claim 5, wherein the material of the two fixingbeads is selected from the group consisting of titanium, gold, andsterling silver.
 7. The intrauterine device of claim 6, wherein thematerial of the two fixing beads is titanium.
 8. The intrauterine deviceof claim 1, wherein an Ag+ ion concentration of the silver nitrate isequal to c.a. 0.00334 mol of Ag⁺.
 9. The intrauterine device of claim 1,wherein the three-dimensional structure is configured to form two ormore contiguous loops of the wire, which are angled with respect to eachother.
 10. The intrauterine device of claim 9, wherein the two or morecontiguous loops of wire are 12 mm to 18 mm in diameter, respectively.11. The intrauterine device of claim 9, wherein the two or morecontiguous loops of wire are configured such that one loop is positionedwithin the plane of the second loop and is angled 60-120 degrees withrespect thereto.
 12. The intrauterine device of claim 1, wherein thewire is made of a super elastic material.
 13. The intrauterine device ofclaim 12, wherein the wire is made of nitinol.